In older adults (70+ years), reduced lean body mass and physical function are associated with increased disability, hospitalization, morbidity and mortality. Because older adults are the fastest growing global subpopulation, identification of mechanisms that underlie the maintenance of lean mass and physical function will be important for addressing the public health priority of healthy aging. Gut bacteria may be involved in mechanisms that underlie the maintenance of lean mass and physical function. In support of this hypothesis, in multiple publications I recently reported significant associations between circulating gut bacteria-related metabolites with these outcomes in older adults. Accordingly, my over- arching hypothesis is that is gut bacteria are associated with and are causatively involved in mechanisms that underlie the maintenance of lean mass and physical function in older adults. To test this hypothesis, I propose to: characterize the association between fecal bacteria with lean mass and physical function (AIM 1), test the causative role of gut bacteria on the maintenance of lean mass and physical function by colonizing germ-free mice with fecal bacteria from older adults (AIM 2), and examine potential mechanisms that link gut bacteria with these outcomes by identifying associations between gut bacteria and serum metabolites with lean mass and physical function (AIM 3). Based on results obtained from the proposed study, I expect to progress towards an independent research career by designing and conducting clinical and translational studies aimed at targeted modulation the gut microflora, which may be a novel and innovative means for improving lean mass and physical function, and for addressing the public health priority of healthy aging in older adults. To accomplish these objectives I will need additional training. The proposed career development plan includes specialized training, coursework, and seminars that will allow me to: 1) learn and apply the bioinformatic methods that are used to analyze and interpret the gut microbiome and serum metabolome, and 2) design and conduct clinical and translational studies aimed at improving lean mass and physical function in older adults. In addition, I have organized a multi-disciplinary mentoring (Drs. Huttenhower, O'Toole and Fielding) and collaborative (Drs. Jones and Garrett) team that has extensive experience in every facet of this project including computational biology, the microbiome, the metabolome, gut bacterial transfer into germ-free mice, and in conducting clinical studies in older adults, which collectively will foster my development in these areas. The knowledge, skills and experience that I will acquire through the proposed career development and research plans of this project are necessary to compete for R-series and other independent investigator grants, thereby allowing me to achieve my career goal of becoming an independent research scientist.